Pharmacologically active enantiomers

ABSTRACT

(S) or (R) enantiomer of a compound of formula: ##STR1## where Alk is an alkyl having from 1 to 3 carbon atoms, and an acid addition salt thereof with a physiologically acceptable acid.

This is a 371 of PCT/EP94/02061 filed Jun. 21, 1994.

DESCRIPTION

This invention relates to pharmacologically active enantiomers, theirsalts with physiologically acceptable acids, a method for theirpreparation and the pharmaceutical compositions containing them.

PCT/EP93/00080 describes a class of novel compounds of the generalformula: ##STR2## where only one of R, R', R" and R'" is an alkyl havingfrom 1 to 3 carbon atoms while the others are hydrogen.

The pharmacological data reported in the above mentioned applicationshow that the compounds of formula (I) are endowed with apharmacological profile similar to that of trazodone (I,R=R'=R.increment.=R'"=H) but also have some advantages such as, forexample, a reduced affinity for adrenergic receptors.

It has now surprisingly been found that both (S) and (R) enantiomers ofthe compounds of formula (I), where R, R', R'" are hydrogen and R" is anaLkyL having from 1 to 3 carbon atoms, have an improved analgesicactivity compared to their racemates.

This finding is even more surprising since both the enantiomers have alower alphalytic activity, and consequently less undesirable effects,compared to the corresponding racemates.

It is therefore a first object of this invention to provide (S) and (R)enantiomers of the compounds of formula: ##STR3## where Alk is an alkylhaving from 1 to 3 carbon atoms, and their addition salts withphysiologically acceptable acids.

Examples of suitable acids are hydrogen chloride, hydrogen bromide,phosphoric acid, sulfuric acid, lactic acid, succinic acid, acetic acid,tartaric acid, malic acid, citric acid, benzoic acid,2-naphthalenesulfonic acid, adipic acid and pimelic acid.

Although both (R) and (S) enantiomers are more active than thecorresponding racemates, (S) enantiomers are more active than (R)enantiomers. Hence, (S) enantiomers are preferred.

As far as the meanings of Alk are concerned, methyl is preferred.

Thus, the preferred compound of this invention is the (S) enantiomer offormula (IA) wherein Alk is methyl.

The analgesic activity of the compounds of this invention has beenproved in mice by means of the phenylquinone test via subcutaneous route(Pharmacol. Exp. Ther., 125, pp 237-240, 1959). Thirty animals weretreated with each product. The experimental results are reported inTable 1.

                  TABLE 1                                                         ______________________________________                                        Compound IA    ANALGESIC ACTIVITY                                             Form        Alk    Phenylguinone, ED.sub.50 (mg/kg)                           ______________________________________                                        Racemate    CH.sub.3                                                                             >12.50                                                     (R)         CH.sub.3                                                                             9.02                                                       (S)         CH.sub.3                                                                             7.80                                                       ______________________________________                                    

Table 1 shows that a higher dose of racemic compound is needed toachieve the same analgesic action. This means that the racemic compoundhas Less analgesic activity compared to the single enantiomers. TabLe 1also shows that (S) enantiomer is more active than (R) enantiomer.

Since an interference with the adrenergic system is an index ofundesirable effects, both the capability of binding to alpha 1adrenergic receptors, as IC₅₀ (TabLe 2), and the alphalytic activity(TabLe 3) of the same compounds have been evaluated.

As far as the receptor binding test is concerned, reference is made to"Moecular Pharmacology", 20, 295-301, (1981).

In turn, the alphalytic activity was evaluated on an isolated organ(deferent of rat) according to the technique described in "Clinical andExperimental Pharmacology & Physiology", 6, 275-279, (1979).

The experimental results are reported in Tables 2 and 3.

                  TABLE 2                                                         ______________________________________                                        Compound IA    Affinity for alpha 1                                           Form        Alk    adrenergic receptors (IC.sub.50)                           ______________________________________                                        Racemate    CH.sub.3                                                                             471                                                        (R)         CH.sub.3                                                                             533                                                        (S)         CH.sub.3                                                                             981                                                        ______________________________________                                    

                  TABLE 3                                                         ______________________________________                                        Compound IA    Alphalytic activity                                            Form        Alk    pA.sub.2                                                   ______________________________________                                        Racemate    CH.sub.3                                                                             7.70 ± 0.7                                              (R)         CH.sub.3                                                                             6.75 ± 0.2                                              (S)         CH.sub.3                                                                             5.40 ± 0.7                                              ______________________________________                                    

In Table 2 the affinity for the alpha 1 adrenergic receptors is as muchhigh as low is the value of IC₅₀, whereas in Table 3, the alphalyticactivity is as much high as high is the value of pA₂, Also the data ofTables 2 and 3 are therefore totally unexpected since they show thatboth the interference with the adrenergic receptor and the alphalyticactivity, and thereby the undesirable effects of both (S) and (R)enantiomers, are lower than those of racemate while the alphalyticactivity of (S) enantiomer is lower than that of (R) enantiomer.

Thus, for the enantiomers and the racemate of formula (IA) the greaterthe analgesic activity the lower the undesired alphalytic activity.

The compounds of this invention can be prepared by fractionalcrystallization of the salts thereof with an optically active acid, andby stereospecific synthesis.

In the first method the salts with tartaric acid proved to beparticularly helpful.

It is therefore a second object of this invention to provide a methodfor the preparation of enantiomers of formula (IA), characterized inthat a racemic compound of formula (IA) is salified with (R,R or S,S)tartaric acid, the pair of the thus obtained diastereoisomeric salts isseparated by fractional crystallization from a suitable solvent, and,when desired, the thus obtained enantiomer is salified with aphysiologically acceptable acid.

Examples of suitable solvents are lower alcohols and water.

The salts of the enantiomers of this invention with (R,R or S,S)tartaric acid are also novel and therefore are a third object of thisinvention.

It is a further object of this invention to provide a method for thestereospecific synthesis of enantiomers of formula (IA) and theiraddition salts with physiologically acceptable acids, characterized inthat a compound of the formula (III): ##STR4## or an alkali metal saltthereof is reacted with a piperazine compound of formula (II): ##STR5##wherein

Alk has the above mentioned meaning, and

X" is a leaving group selected from the group comprising

chlorine, bromine and --O--SO₂ -Z where Z is alkyl or aryl, and Compound(II) has the absolute (R) or (S) configuration, in the presence of asuitable organic diluent or a mixture of organic diluents at atemperature of from 40° C. to the boiling temperature of the reactionmixture, and, when desired, the thus obtained enantiomer is salifiedwith a physiologically acceptable acid.

The above mentioned reaction essentially involves the alkalinization ofa secondary amino group and may be carried out according to conventionaltechniques (J. March, Advanced Organic Chemistry, 3rd ed., J. Wiley &Sons, N.Y., pages 364-365).

Preferably, the compound of formula (III) is reacted in the form of analkaline salt such as, for example, the sodium salt described by U.S.Pat. No. 3,381,009.

Typical meanings of Z are methyl, phenyl, tolyl and p-bromo-phenyl.

The reaction is preferably carried out by reacting the sodium salt ofthe compound of formula (III) with a compound of formula (II) in thepresence of a suitable organic diluent or a mixture of organic diluentsat a temperature of from 40° C. to the boiling temperature of thereaction mixture. Examples of suitable organic diluents are: aromatichydrocarbons, aliphatic alcohols, amides and mixtures thereof.

Examples of preferred aromatic hydrocarbons are benzene, toluene andxylene. Examples of aliphatic alcohols are butanol, t-butanol,s-butanol, isobutanol, pentanol and t-pentanol. A typical example of apreferred amide is dimethylamide.

In turn, the stereospecific synthesis of the compounds of formula (II)can be performed by reacting a compound of formula ##STR6## where Alkhas the above mentioned meaning,

X' is CH₃ --O--SO₂ --O-- or halogen, and

Y is an alkyl having from 1 to 3 carbon atoms,

having the absolute (S) or (R) configuration, with the compound offormula ##STR7## to yield a compound of formula ##STR8## where Y and Alkhave the above described meaning, having (R) absolute configuration whenthe Compound VIII has (S) configuration and viceversa.

The reaction between Compound (VIII) and Compound (VII) to yieldCompound (VI) is preferably carried out in the presence of an acidacceptor and a suitable solvent.

Examples of suitable acid acceptors are triethylamine and pyridine.

Examples of suitable solvents are the aromatic hydrocarbons such astoluene and xylene.

Compound (VI) is then cyclized to yield a compound of formula ##STR9##having the same absolute configuration as Compound (VI).

The cyclization of Compound (VI) to Compound (V) could not be performedwith the technique described in PCT/EP93/00080 in connection with thecorresponding racemic compounds since said technique caused completeracemization. After a number of unsuccessful attempts which Led eitherto racemization or to recovery of unaltered Compound (VI), it wasunexpectedly found that the desired cyclization could be very easilyperformed by dissolution of Compound (VI) in an aqueous solution of astrong acid and separation, after a brief heating, of the desiredCompound (V) by alkalinization of the resultant solution.

A typical example of a preferred strong acid is hydrochloric acid.

Compound (V) thus obtained is then reduced in a manner similar to thatdescribed for the reaction Scheme 3 in the above mentioned patentapplication PCT/EP93/00080.

The prepararation is then prosecuted in a manner similar to thatdescribed in the above mentioned patent application in relation to thereaction Scheme 2.

Both during the cyclization step (VI→VI) and during all the subsequentsteps there is no inversion of the configuration and the thus obtainedfinal compound of formula (IA) has the same absolute configuration asCompound (V). The possibible racemization, if any, is very small.

For practical purposes the compounds of this invention may beadministered as they are but it will be preferred to administer them aspharmaceutical compositions.

These compositions are a further object of this invention and contain atherapeutical amount of at least one enantiomer of formula (IA) or of anaddition salt thereof with a physiologically acceptable acid, togetherwith liquid or solid pharmaceutical carriers.

The pharmaceutical compositions of this invention may be solid, such astablets, sugar-coated pills, capsules, powders and controlled releaseforms, or semi-liquid, such as creams and ointments, or liquid, such assolutions, suspensions and emulsions.

In addition to conventional carriers, the compositions of this inventionmay contain other suitable pharmaceutical additives, such aspreservatives, stabilizers, emulsifiers, salts to regulate osmoticpressure, buffers, colouring and flavouring agents.

If required for a particular therapy, the compositions of this inventionmay also contain other compatible active ingredients, whosecontemporaneous administration is therapeutically useful.

For therapeutical purposes the effective amount of the enantiomer offormula (IA) to be administered can vary widely depending on variousfactors such as the particular therapy required, the pharmaceuticalcomposition, the method of administration and the effectiveness of thespecific enantiomer of this invention that is used. Nevertheless, theoptimal effective amount can be chosen by simple routine procedures.

In general, the daily posology of the enantiomers of formula (IA)preferably ranges from 0.1 to 10 mg/kg.

The pharmaceutical compositions of this invention can be preparedaccording to conventional techniques known to the pharmaceuticalchemist, which comprise admixing, granulating and compressing, whennecessary, or variously mixing and dissolving the ingredients, whenappropriate to obtain the desired result.

The following examples are intended to illustrate this invention.

EXAMPLE 1

A mixture of 12.5 g (0.032 moles) of racemate (I, R=R'=R'"=H; R"=CH₃),as a base, and 4.8 g (0.032 moles) of naturally occuring (R,R) tartaricacid in 125 ml of absolute ethyl alcohol, was briefly heated at almostboiling temperature until dissolution was complete.

The solid separated by cooling was collected by filtration andrecrystallized from absolute ethyl alcohol until a constant meltingpoint was obtained.

m.p. 151°-152° C., alpha!_(D) ²⁰ =+13.2±0.3 (1% in water).

The corresponding base was obtained by suspension of the salt in waterand alkalinization, under stirring, with powdered potassium carbonate.

The residue of the extraction with dichloromethane melts at 63°-65° C.(hexane), alpha!_(D) ²⁰ =+32.0±0.3 (1% in absolute ethyl alcohol).

Hydrochloride, m.p. 122°-124° C. (from ethyl alcohol, hygroscopic);

Sulfate, m.p. 204°-205° C.;

Maleate, m.p, 142°-143° C.

(R) base was recovered from the filtered solution, from which the (S)(R,R) salt had been previously separated, and was dissolved in absoluteethyl alcohol.

An equimolar amount of (S,S) tartaric acid was then added to thissolution. The (R) (S,S) salt was separated by cooling. This salt has thesame melting point (151°-152° C.) as the (S) (R,R) salt, alpha!_(D) ²⁰=-13.2±0.3.

The corresponding base melts at 63°-65° C.; alpha!_(D) ²⁰ =-32.0±0.3 (1%in ethyl alcohol).

Hydrochloride, m.p. 122°-124° C. (hygroscopic).

EXAMPLE 2 a) (R)-1-(3-chlorophenyl)-3-methyl-piperazin-2-one

(formula V, Alk=CH₃)

A solution of 18.4 g (0.108 moles) of N-(3-chlorophenyl)-ethanediamine(J. Med. Chem., 9, 858-860 (1966)), 19.3 ml (0.119 moles) of(S)-methanesulfonyl-lactic acid ethyl ester and 22.8 ml (0.163 moles) oftriethylamine in 200 ml of toluene was boiled and refluxed overnight.

The reaction mixture was washed with water and extracted with a solutionof 1N hydrochloric acid. The aqueous phase was alkalinized with powderedpotassium carbonate and extracted with methylene chloride.

The thus obtained base was purified by flash chromatography (silica gel,hexane-ethyl acetate 1:1).

The oily residue obtained after evaporation of the solvent was dissolvedin 10 parts (by weight) of 2N HCl and the resultant solution was boileduntil the starting material disappeared (TLC).

The desired product, alpha!_(D) ²⁰ =+50.0 was separated byalkalinization with an alkaline carbonate (sodium or potassium).

b) (R)-2- 3-4-(3-chlorophenyl)-1-(2-methyl)-piperazinyl!-propyl!-1,2,4-triazol4,3-a!-pyridine-3(2H)-one

(formula IA, Alk=CH₃)

The title product was prepared, starting from the compound prepared inthe previous step (a), in a manner similar to that described in thepatent application PCT/EP93/00080.

Base, alpha!_(D) ²⁰ =-31.8 (1% in ethyl alcohol) .

Hydrochloride, m.p. 122°-124° C. (also in admixture with a sampleprepared according to Example 1).

The (R)-1-(3-chlorophenyl)-3-methylpiperazine intermediate (formula IV,Alk=CH₃) has a rotatory power alpha!_(D) ²⁰ =+15.0 (1% in ethylalcohol).

EXAMPLE 3 (S)-2- 3-4-(3-chlorophenyl)-1-(2-methyl)-piperazinyl!-propyl!-1,2,4-triazol4,3-a!-pyridine-3(2H)-one

(formula IA, Alk=CH₃)

The title product was prepared in a manner similar to that described inExample 2 above except for the substitution of(S)-methanesulfonyl-lactic acid ethyl ester with an equimolar amount of(R)-2-bromo-propionic acid ethyl ester.

Base, m.p. 63°-65° C., alpha!_(D) ²⁰ =+32.0±0.3 (1% in ethyl alcohol).

We claim:
 1. A method for preparing an enantiomer of formula (IA)##STR10## where Alk is an alkyl having from 1 to 3 carbon atoms, or anacid addition salt thereof with a physiologically acceptableacid,characterized in that (a) a racemic mixture of formula (IA) issalified with (R,R or S,S) tartaric acid, (b) the pair of the thusobtained diastereoisomeric salts is separated by fractionalcrystallization from a suitable solvent, and, when desired, (c) the thusobtained enantiomer is salified with a physiologically acceptable acid.2. A method according to claim 1, characterized in that the solvent usedin step (b) is a lower alcohol or water.
 3. A method to cyclize acompound of formula ##STR11## where Y and Alk, the same or different,are an alkyl having from 1 to 3 carbon atoms,having (R) or (S)configuration, to yield a compound of formula ##STR12## having the sameabsolute configuration as Compound (VI), characterized in that thecyclization reaction is performed in the presence of an aqueous solutionof a strong acid and that the desired Compound (V) is obtained, after abrief heating, by alkalinization of the resultant solution.
 4. A methodaccording to claim 3, characterized in that the strong acid ishydrochloric acid.